Dehydroeburicoic Acid, a Dual Inhibitor against Oxidative Stress in Alcoholic Liver Disease

Shasha Cheng; Yi Kuang; Guodong Li; Jia Wu; Chung Nga Ko; Wanhe Wang; Dik Lung Ma; Min Ye; Chung Hang Leung

doi:10.3390/ph16010014

Dehydroeburicoic Acid, a Dual Inhibitor against Oxidative Stress in Alcoholic Liver Disease

Shasha Cheng, Yi Kuang, Guodong Li, Jia Wu, Chung Nga Ko, Wanhe Wang, Dik Lung Ma^*, Min Ye^*, Chung Hang Leung^*

^*Corresponding author for this work

Department of Chemistry

Research output: Contribution to journal › Journal article › peer-review

2 Citations (Scopus)

Abstract

Alcoholic liver disease (ALD) is a complicated disease which can lead to hepatocellular carcinoma; however, there is a lack of satisfactory therapeutics. Dehydroeburicoic acid (DEA) (1), a triterpenoid isolated from Antrodia cinnamomea, has been reported to act against ALD, but its mechanisms of action are still not clear. In this study, we report for the first time the use of DEA (1) as a dual inhibitor of the Keap1–Nrf2 protein–protein interaction (PPI) and GSK3β in an in vitro ALD cell model. DEA (1) engages Keap1 to disrupt the Keap1–Nrf2 PPI and inhibits GSK3β to restore Nrf2 activity in a Keap1-independent fashion. DEA (1) promotes Nrf2 nuclear translocation to activate downstream antioxidant genes. Importantly, DEA (1) restores the mitochondrial dysfunction induced by ethanol and generates antioxidant activity in the ALD cell model with minimal toxicity. We anticipate that DEA (1) could be a potential scaffold for the further development of clinical agents for treating ALD.

Original language	English
Article number	14
Journal	Pharmaceuticals
Volume	16
Issue number	1
DOIs	https://doi.org/10.3390/ph16010014
Publication status	Published - Jan 2023

Scopus Subject Areas

Molecular Medicine
Pharmaceutical Science
Drug Discovery

User-Defined Keywords

alcoholic liver disease (ALD)
glycogen synthase kinase 3β (GSK3β)
hepatoprotective
Keap1–Nrf2 protein–protein interaction (PPI)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.3390/ph16010014

Cite this

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title = "Dehydroeburicoic Acid, a Dual Inhibitor against Oxidative Stress in Alcoholic Liver Disease",

abstract = "Alcoholic liver disease (ALD) is a complicated disease which can lead to hepatocellular carcinoma; however, there is a lack of satisfactory therapeutics. Dehydroeburicoic acid (DEA) (1), a triterpenoid isolated from Antrodia cinnamomea, has been reported to act against ALD, but its mechanisms of action are still not clear. In this study, we report for the first time the use of DEA (1) as a dual inhibitor of the Keap1–Nrf2 protein–protein interaction (PPI) and GSK3β in an in vitro ALD cell model. DEA (1) engages Keap1 to disrupt the Keap1–Nrf2 PPI and inhibits GSK3β to restore Nrf2 activity in a Keap1-independent fashion. DEA (1) promotes Nrf2 nuclear translocation to activate downstream antioxidant genes. Importantly, DEA (1) restores the mitochondrial dysfunction induced by ethanol and generates antioxidant activity in the ALD cell model with minimal toxicity. We anticipate that DEA (1) could be a potential scaffold for the further development of clinical agents for treating ALD.",

keywords = "alcoholic liver disease (ALD), glycogen synthase kinase 3β (GSK3β), hepatoprotective, Keap1–Nrf2 protein–protein interaction (PPI)",

author = "Shasha Cheng and Yi Kuang and Guodong Li and Jia Wu and Ko, {Chung Nga} and Wanhe Wang and Ma, {Dik Lung} and Min Ye and Leung, {Chung Hang}",

note = "This work is supported by the Science and Technology Development Fund (Macau SAR, China) (0007/2020/A1, 0020/2022/A1), the State Key Laboratory of Quality Research in Chinese Medicine (University of Macau) (SKL-QRCM(UM)-2020-2022), the University of Macau (University of Macau) (MYRG2019-00002-ICMS, MYRG2020-00017-ICMS), 2022 Internal Research Grant of SKL-QRCM (University of Macau) (QRCM-IRG2022-011), the National Natural Science Foundation of China, China (22077109, 21775131 and 82073715), the HKBU SKLEBA Research Grant (SKLP_2223_P03). Publisher Copyright: {\textcopyright} 2022 by the authors.",

year = "2023",

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doi = "10.3390/ph16010014",

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volume = "16",

journal = "Pharmaceuticals",

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T1 - Dehydroeburicoic Acid, a Dual Inhibitor against Oxidative Stress in Alcoholic Liver Disease

AU - Cheng, Shasha

AU - Kuang, Yi

AU - Li, Guodong

AU - Wu, Jia

AU - Ko, Chung Nga

AU - Wang, Wanhe

AU - Ma, Dik Lung

AU - Ye, Min

AU - Leung, Chung Hang

N1 - This work is supported by the Science and Technology Development Fund (Macau SAR, China) (0007/2020/A1, 0020/2022/A1), the State Key Laboratory of Quality Research in Chinese Medicine (University of Macau) (SKL-QRCM(UM)-2020-2022), the University of Macau (University of Macau) (MYRG2019-00002-ICMS, MYRG2020-00017-ICMS), 2022 Internal Research Grant of SKL-QRCM (University of Macau) (QRCM-IRG2022-011), the National Natural Science Foundation of China, China (22077109, 21775131 and 82073715), the HKBU SKLEBA Research Grant (SKLP_2223_P03). Publisher Copyright: © 2022 by the authors.

PY - 2023/1

Y1 - 2023/1

N2 - Alcoholic liver disease (ALD) is a complicated disease which can lead to hepatocellular carcinoma; however, there is a lack of satisfactory therapeutics. Dehydroeburicoic acid (DEA) (1), a triterpenoid isolated from Antrodia cinnamomea, has been reported to act against ALD, but its mechanisms of action are still not clear. In this study, we report for the first time the use of DEA (1) as a dual inhibitor of the Keap1–Nrf2 protein–protein interaction (PPI) and GSK3β in an in vitro ALD cell model. DEA (1) engages Keap1 to disrupt the Keap1–Nrf2 PPI and inhibits GSK3β to restore Nrf2 activity in a Keap1-independent fashion. DEA (1) promotes Nrf2 nuclear translocation to activate downstream antioxidant genes. Importantly, DEA (1) restores the mitochondrial dysfunction induced by ethanol and generates antioxidant activity in the ALD cell model with minimal toxicity. We anticipate that DEA (1) could be a potential scaffold for the further development of clinical agents for treating ALD.

AB - Alcoholic liver disease (ALD) is a complicated disease which can lead to hepatocellular carcinoma; however, there is a lack of satisfactory therapeutics. Dehydroeburicoic acid (DEA) (1), a triterpenoid isolated from Antrodia cinnamomea, has been reported to act against ALD, but its mechanisms of action are still not clear. In this study, we report for the first time the use of DEA (1) as a dual inhibitor of the Keap1–Nrf2 protein–protein interaction (PPI) and GSK3β in an in vitro ALD cell model. DEA (1) engages Keap1 to disrupt the Keap1–Nrf2 PPI and inhibits GSK3β to restore Nrf2 activity in a Keap1-independent fashion. DEA (1) promotes Nrf2 nuclear translocation to activate downstream antioxidant genes. Importantly, DEA (1) restores the mitochondrial dysfunction induced by ethanol and generates antioxidant activity in the ALD cell model with minimal toxicity. We anticipate that DEA (1) could be a potential scaffold for the further development of clinical agents for treating ALD.

KW - alcoholic liver disease (ALD)

KW - glycogen synthase kinase 3β (GSK3β)

KW - hepatoprotective

KW - Keap1–Nrf2 protein–protein interaction (PPI)

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U2 - 10.3390/ph16010014

DO - 10.3390/ph16010014

M3 - Journal article

AN - SCOPUS:85146805811

SN - 1424-8247

VL - 16

JO - Pharmaceuticals

JF - Pharmaceuticals

IS - 1

M1 - 14

ER -

Dehydroeburicoic Acid, a Dual Inhibitor against Oxidative Stress in Alcoholic Liver Disease

Abstract

Scopus Subject Areas

User-Defined Keywords

UN SDGs

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